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Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p<0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p<0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Purpose: The purpose of this study was to compare the height of velopharyngeal (VP) closure in relation to the palatal plane between individuals with velopharyngeal insufficiency (VPI) with or without cleft palate and individuals without cleft palate and with normal speech, considering the effects of age and sex. Method: Magnetic resonance imaging was used to analyze the height of VP closure in the midsagittal view during phonation of /i/ and /s/ sounds among 105 individuals with VPI and 45 individuals without cleft palate and normal speech. Results: Independent-samples t tests demonstrated that individuals with VPI display a significantly lower mean height of VP closure (3.7 mm) compared to individuals without cleft palate and normal speech during phonation of /i/ and /s/ sounds ( p < .001). Analysis of variance was used to evaluate the impact of age and sex on the height of VP closure. Significant differences were observed between the height of VP closure in individuals with VPI and those without cleft palate and normal speech across the age span during the production of /i/ and /s/ sounds. However, nonsignificant differences were found between the height of VP closure in males and females of the VPI group and those without cleft palate and normal speech during the production of these sounds. Conclusions: The results revealed the variations of the height of VP closure in relation to the palatal plane. These findings provide insights into the presurgical planning for individuals with VPI undergoing palatal surgeries, especially the location of pharyngeal flap insertion.

Background: The impact of computer ECG interpretation (CEI) on medical professionals’ performance is understudied. This study aims to assess the interpretation proficiency of diverse medical professionals with and without access to CEI reports. Methods: Medical professionals from diverse backgrounds interpreted 60 12-lead ECGs with urgent and non-urgent findings. The interpretation process involved two interpretation phases: (i) 30 ECGs with clinical statements and (ii) the same 30 ECGs and clinical statements in random order along with a CEI report. Diagnostic performance was evaluated based on interpretation accuracy, time per ECG, and self-reported confidence (rated 0 [not confident], 1 [somewhat confident], or 2 [confident]). Results: Among 892 participants, there were 44 (4.9%) primary care physicians, 123 (13.8%) cardiology fellows-in-training, 259 (29.0%) resident physicians, 137 (15.4%) medical students, 56 (6.3%) advanced practice providers, 82 (9.2%) nurses, and 191 (21.4%) allied health professionals. The inclusion of the CEI significantly improved interpretation accuracy by 15.1% (95% CI, 14.3 to 16.0; P<0.001), reduced interpretation time by 52 seconds (95% CI, -56 to -48; P<0.001), and increased confidence by 0.06 (95% CI, 0.03 to 0.09; P=0.003) (Table 1) . Conclusions: CEI integration improves ECG interpretation accuracy, efficiency, and confidence across medical professionals. Nevertheless, even with CEI, significant gaps in ECG interpretation proficiency remain.

Background: Accurate ECG interpretation is vital, but variations in skills exist among healthcare professionals. This study aims to identify factors contributing to ECG interpretation proficiency. Methods: Survey data and ECG test scores from participants in the EDUCATE Trial were analyzed. The dependent variable was the test score for interpreting 30 12-lead ECGs. Independent variables included non-modifiable factors (physician status, clinical experience, patient care impact) and modifiable factors (weekly interpretations, training hours, expert supervision frequency). Bivariate and multivariate analyses generated the Comprehensive Model (all factors) and Actionable Model (modifiable factors only). Results: Among 1206 participants, there were 72 (6.0%) primary care physicians, 146 (12.1%) cardiology fellows-in-training, 353 (29.3%) resident physicians, 182 (15.1%) medical students, 84 (7.0%) advanced practice providers, 120 (9.9%) nurses, and 249 (20.7%) allied health professionals. Physicians accounted for 571 (47.3%) of participants, while 453 (37.6%) were non-physicians. Bivariate analysis showed associations between test scores and multiple variables (Table 1) . In the Comprehensive Model, scores were independently associated with weekly interpretations (9.9 score increase; 95% CI 7.9-11.8; P<0.001), physician status (9.0 score increase; 95% CI 7.2-10.8; P<0.001), and training hours (5.7 score increase; 95% CI 3.7-7.6; P<0.001). In the Actionable Model, scores were independently associated with weekly interpretations (12.0 score increase; 95% CI, 10.0-14.0; P<0.001) and training hours (4.7 score increase; 95% CI 2.6-6.7; P<0.001). The Comprehensive and Actionable Models accounted for 18.7% and 12.3% of the variance in test scores, respectively. Conclusions: Being a physician is a non-modifiable predictor, while training and regular practice are modifiable predictors of ECG interpretation performance.

Background: Gaps in ECG interpretation competency among medical professionals exist, with a need for practical, evidence-based, and accessible learning solutions. We conducted an international, prospective, randomized controlled trial to assess the effectiveness of web-based, self-directed ECG learning. Methods: A total of 1206 diverse medical learners and professionals underwent an initial test, followed by random assignment to one of four groups: (i) online question-bank (questions), (ii) online lectures (lectures), (iii) online, question-bank and lectures (hybrid), or (iv) no resources (control). After 4 months, a post-test was administered to evaluate the overall change in performance. Results: Of all participants, 863 (72%) completed the trial. After the 4-month follow-up, all three online, self-directed intervention groups (questions, lectures, and hybrid) showed significant improvement in overall performance (P<0.001), while the control group did not (P=0.544). The questions, lectures, and hybrid interventions demonstrated score improvements of +11.4% (95% CI, 9.1-13.7; P<0.001), +9.8% (95% CI, 7.8-11.9; P<0.001), and +11.0% (95% CI, 9.2-12.9; P<0.001) respectively, compared to +0.8% (95% CI, -1.2-2.8; P=0.544) for the control group. These improvements were consistent across medical professional groups (Figure 1) . Conclusions: Web-based, self-directed learning resources effectively improved ECG interpretation proficiency for diverse medical learners and professionals.

Background: ECG interpretation is crucial in medical practice, but professionals struggle with achieving and maintaining competency. Identifying proficiency gaps aids in designing educational interventions. Methods: Medical professionals from various disciplines interpreted 30 12-lead ECGs containing commonly taught urgent and non-urgent findings. Performance metrics evaluated were overall adjusted score (% of correctly identified findings using a point-value score based on clinical relevance), unadjusted score (% of correctly identified findings), interpretation time per ECG, and self-reported confidence (rated on an ordinal scale of 0 [not confident], 1 [somewhat confident], or 2 [confident]). Results: Among 1206 participants, there were 72 (6%) primary care physicians (PCPs), 146 (12%) cardiology fellows-in-training (FIT), 353 (29%) resident physicians, 182 (15%) medical students, 84 (7%) advanced practice providers (APPs), 120 (10%) nurses, 249 (21%) allied health professionals, 571 (47%) physicians, and 453 (38%) non-physicians. Participants had a mean adjusted score of 46.9% (± 15.9%), unadjusted score of 56.4% (± 17.2%), interpretation time of 142 seconds (± 67 seconds), and confidence of 0.83 (± 0.53) (Table 1) . Performance varied across groups; cardiology FIT had superior performance in all metrics. Physicians generally outperformed non-physicians, with higher overall adjusted score (52% vs. 43%; p<0.01), unadjusted score (62% vs. 52%; p<0.01), and confidence (0.91 vs. 0.80; p<0.01). Unadjusted score for PCPs was higher than nurses and APPs (58% vs. 47% and 51%; p<0.01) but lower than resident physicians (58% vs. 60%; p<0.01). Allied health professionals outperformed nurses and APPs and closely matched resident physicians and PCPs. Conclusions: Significant gaps in ECG interpretation proficiency exist, emphasizing the need for comprehensive, scalable, and accessible educational tools.

ObjectiveErdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study.MethodsAfter quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed.ResultsA signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.ConclusionOverall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.image

Background: Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy. Methods: In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors. Results: Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: <1 year, 26%; 1 to 5 years, 37%; >5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (−0.5±2.4 %/year, P = 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus −1.0±2.2, P = 0.006). Additionally, IPH was associated with a decrease in lumen area (−0.4±0.9 mm2/year versus 0.3±1.4, P = 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0, P < 0.001). Conclusions: Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01178320.

Background: Although vulnerable plaques are considered the pathological substrate for acute cardiovascular events, the pursuit of imaging surrogate markers for systemic atherothrombotic risk is currently focused on plaque burden. The prognostic value of vulnerable plaque characteristics as novel markers for systemic cardiovascular outcomes remains elusive. Advances in magnetic resonance imaging (MRI) have enabled characterization of the vulnerable carotid plaque. In a prospective study, we tested whether MRI-detected carotid plaque characteristics predict subsequent cardiovascular events. Methods: As part of an event-driven clinical trial, subjects with clinically established atherosclerotic disease were recruited. A multi-sequence protocol was used to measure the volumes of calcification and necrotic core (NC), and to identify the presence of intraplaque hemorrhage (IPH) and thin/ruptured fibrous cap (FC) using published criteria. The primary endpoint included fatal and non-fatal myocardial infarction or ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization. Cox regression analysis was used to present results as hazard ratio (HR) with 95% confidence interval (CI). Results: Of 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (mean age: 61±9 years; male: 82%; statin use: 94%). Calcification, NC, IPH, and thin/ruptured FC were detected in 48%, 52%, 8% and 14% of subjects, respectively. During a median follow-up of 35.1 months, 18 (8.4%) subjects reached the primary endpoint. MRI-detected plaque characteristics associated with the primary endpoint included larger NC (HR per 1 standard deviation increase in volume [1-SD]: 1.43 [1.16, 1.75], p<0.001), thin/ruptured FC (HR: 4.31 [1.67, 11.12], p=0.003), and marginally IPH (HR: 3.00 [0.99, 9.13], p=0.053). Although calcium deposition is traditionally pursued as a marker for atherosclerosis, subjects with larger calcification (HR per 1-SD: 0.60 [0.26, 1.41], p=0.20) did not show increased risk. Conclusions: Vulnerable plaque characteristics are prevalent in carotid arteries of patients with established atherosclerosis and are predictive of systemic cardiovascular outcomes.

Abstract Qualitative disorders of platelets are often missed at clinical evaluation. Hermansky-Pudlak (HPS) syndrome is a rare genetic metabolic disorder with subtype specific clinical associations most prevalent in Puerto Rico with strong link to consanguinity. HPS is usually associated with albinism, visual impairment and a qualitative platelet dysfunction due to absence of dense granules. Ceroid accumulation can be associated with inflammatory bowel disease, pulmonary fibrosis and kidney disease. Ten variants have been described with types 1, 2 and 4 associated with severe disease whilst type 3, 5 and 6 is associated with mild disease. Little is known about types 7, 8, 9 and 10. A Caucasian adult female presented with a history of intermittent episodes of severe bleeding. She carried the diagnosis of probable von Willebrand's disease at presentation. This particular patient did not respond to cryoprecipitate infusion but bleeding stopped secondary to infusion of normal platelets, a clue to a platelet storage disorder. Hence she was re-investigated for a bleeding disorder and initial coagulation testing identified abnormal platelet aggregation and amplitude pattern to epinephrine. She was subsequently evaluated with platelet transmission electron microscopy and platelet flow cytometry at the Mayo Clinic Hematopathology. Platelet TEM showed complete absence of dense granules and a normal flow cytometry. HPS was suspected and initial genetic studies identified a variant genetic abnormality. Further studies were done at the NIH. Classical clinical features of HPS like nystagmus, and ocular albinism was not identified at initial neurological and ophthalmologic examination. But more detailed evaluation revealed subclinical oculocutaneous albinism. Genome wide SNP analysis showed regions of homozygosity including HPS 1 and HPS 6; deletions were not identified in these genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant [c.383T>C (p.V128A)] in HPS6. Reduced HPS6 mRNA levels were found in the patient's skin fibroblasts compared to cells from patients with HPS-1 and normal control cells. HPS6 protein expression in the patient's cells was also low and approximately 60% lower than that of normal cells. HPS is a rare platelet storage disorder that can often be missed. Platelet aggregation tests need to be followed up by platelet TEM and genetic testing to definitively diagnose this condition. Further work up has defined a new missense variant by SNP analysis, next generation sequencing and fibroblast culture. It is important to identify the subtype of HPS, because certain subtypes of HPS (HPS 1, 2 and 4) have clinical manifestations like progressive pulmonary fibrosis. Identification of the platelet storage disorder also helps in management of the bleeding diathesis. Disclosures No relevant conflicts of interest to declare.